Abstract 1590: A preclinical mammary intraductal model to study early stage human breast cancer

Abstract

Abstract Our goal is to develop a murine intraductal mammary model to examine the progression of early stage human breast cancer. Current models include injection of human mammary epithelial cell lines into the mammary fat pad (MFP) of immunocompromised mice or intraductal injection via cleaved nipple. With the MFP model, these cells are injected into the correct anatomical location for primary invasive tumors but do not form in the location of initiation, i.e., the mammary ducts. Intraductal models allow direct study of tumor cell formation and dissemination from mammary ducts; however, surgical manipulations performed to expose the teat canal are confounded by wound healing and inflammatory programs that are reported to be tumor promotional in other contexts. Our intraductal model of human breast cancer delivers human mammary tumor cells directly through the mouse teat into the correct anatomical location for ductal in situ carcinoma (DCIS) without surgical manipulations. Further, our model provides co-evolution of tumor progression with stromal changes versus the MFP model where the stroma responds to tumor cells at time of injection. Using the bi-potential progenitor MCF10ADCIS.com cell line and harvesting tissue 4 weeks post-injection, we corroborate reported studies showing DCIS lesions with distinct characteristics of the main human subtypes and progression to invasive disease. Immunohistochemical (IHC) analysis shows that these cells incorporate into the mouse mammary ducts and form E-cadherin-based junctional complexes with neighboring cells, including other human tumor cells or normal mouse epithelial cells. Although these cells have been characterized as estrogen receptor (ER) negative both in vitro and in vivo, IHC revealed that some tumors developed within our model were ER positive according to the Allred scoring method. Our model permits a rigorous evaluation of the effects that physiologic-induced changes in mammary tissue remodeling (i.e. postpartum involution) has on tumor progression. We investigated tumor incidence and burden in the postpartum involution setting and found much greater increases in the involution group compared to the respective nulliparous control group. Interestingly, the Ki67 proliferative index is lower in the involution compared to the respective nulliparous control, suggesting a mechanism other than proliferation is driving tumor promotion in the postpartum setting. In summary, our murine intraductal model of human breast cancer provides a rigorous approach to studying early stage tumor progression. This model is particularly suited to studying host effects on tumor progression and future studies will determine the effects of physiological endocrine status on tumor cell dissemination from mammary ducts. Since mammary ducts are the primary sites of occult tumors in women, we propose that this teat injection model will be a more relevant model for all stages of human disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1590. doi:10.1158/1538-7445.AM2011-1590